3-alkanoyl 1-tertiary-amino-alkyl indol oximes and production thereof



I; in,

Unitedsrates P s-ALKANoYL l-TERTIARY-AMINO-ALKYL INDOL} OXIMES AND-PRODUCTION THEREOF Josef Schmitt, lHay-les-Roses, France, assignor to Etablissements Clin-Byla (Societe anonyme), Paris, France, a, company of France No Drawing. Application July 17, 1958 Serial No. 749,074

Claims priority, application France August 3, 1956 6 Claims. (Cl. 260-319) This application is a continuation-in-part of my cation Serial No. 674,298, now abandoned.

' In my copending U.S. patent application Serial No. 575,005, filed March 30, 1956, I have described certain N-tertiary-amino-alkyl phenothiazines having an acyl group or oxo-alkyl in the Ii-position of the phenothiazine nucleus, and the production thereof by decarboxylating N-tertiary-amino alkyl esters of the corresponding phenothiazine- N-carboxylic acids. In my copending U.S. patent application Serial No. 663,916, filed June 6, 1957,

appliand now abandoned, I have described another process for producing the same and related compounds; according to that process an acyl phenothiazine, in particular a 3'-acyl phenothiazine, is condensed with a tertiary-amino alkyl halide with or without transitory blocking of the oxo-group in the acyl side chain.

I have now found that other heterocyclic compounds having an acyl substituent attached to the nucleus and a nuclear nitrogen atom which bears a tertiary-amino alkyl chain are also highly desirable for therapeutic purposes or as intermediate products for the production ofcompounds useful for therapeutic purposes.

Broadly stated myinvention comprises basic derivatives of pyrrol and benzo pyrrols which bear a tertiaryamino alkyl chain attached to the nuclear nitrogenatom and an acyl (oxo-alkyl or oxo-phenyl-alkyl) group attached to a nuclear carbon atom, their acid addition salts, their quaternary ammonium derivatives and the corresponding oximes.

v Patented Mar.

wherein R is selected from the class consisting of H;- a a s, s u t a and a R is an alkylene group having 2 or 3 carbon atoms and Am is selected from the class consisting of dimethylamino, diethylamino, morpholino, pyrrolidino,piperidino, piperazino, and N -methyl piperaz'ino groups especiallythose in which R is H or an alkyl group having from corresponding to 3-formyl, 3-a'cetyl,"3-n-propiony1, 3-n- More particularly, my. invention comprisesfpyrrol,

indol (or benzo pyrrol) and carbazol (or dibenzo pyrrol) derivatives having the characteristicsabove indicated and bearing an acyl (oxo-alkyl or oxo-phenylealkyl) group in any position, more particularly in the 2 (or a)-position, the 3-position and the 2-position respectively, and also their acid addition salts, ,their quaternary. ammonium derivatives and the corresponding oximes.

As example, I shall mention 2-propionyl l-ot-dimethyl- I amino-propyl pyrrol and themethiodide thereof, 3-propionyl l-a-dimethylamino-propyl indol, the methiodide and the acid maleate thereof and the corresponding oxime, 3-formyl l fl-dimethylamino-ethyl indol and the acid maleate thereof and the corre' sponding oxime, 3-acety1 l-fl-dimethylamino-ethyl ,indol and .the acid maleate thereof, the corresponding oxime and the acid maleate of said oxime, 3-n-propion'yl "l-B-dimethylamino-ethyl indol, the methiodide and the acid maleate thereof, the corresponding oxime and the acid maleate of said oxime, 3-n-butyryll-fl-dimethylamino-ethyl indol and the acid maleatethereof, the corresponding oxime and the acid maleate of said oxime, 3-valeroyl l-fl-dimethylaminoethyl indol and the acid maleate thereof, the corresponding oxime and the acid maleate of said oxime, 3-phenylacetyl l -fl-dimethylamino-ethyl indol and the acid maleate thereof and the corresponding oxime, propionyl l-s-diethylamino-ethyl indol and the acid maleate thereof, 3- propionyl 1-(fi-methyl-fl-dimethylamino)-ethyl indol and the acid maleate thereof, the corresponding oxime, 2-

'1 to 4 carbonatoms'while Am is ethylamino. V I As a matter of fact, particularly desirable for thera dimethylamino or dipeutic purposes as vasoconstrictive, agentsare the oximes butyryl and 3-n-valeroyl l-B-dimethylamino-ethyl indol, more particularly to 3-acetyl, 3-n-propio'nyl fand 341 butyryl 1-fl-dimethylamino-ethyl indol, and the acid-addif tion salts thereof with pharmaceutically, acceptable acids; While acid maleates of such oximes are particularly convenient in being easily produced in crystalline form' and being readily soluble in water, other acid addition salts with pharmaceutically acceptable" acids, for example hydrochloric acid, phosphoric acid, sulphuric acid, oxalic acid, furnan'c acid, succinic acid,v citric acid, tartaric acid, gluconic acid may also be employed.

My invention further comprises a process for the production of basic derivatives of pyrrol and benzo pyrrols defined "as above, wherein an acyl pyrrol or acyl benzo pyrrol is condensed with a tertiary-amino alkyl halide preferably in an inert organic medium in the presence of an. alkaline condensation agent. The reaction PTO. ceeds with a verygood yield where the acyl-groupcontains 3 or more carbon atoms and a less good yield where the acyl group contains less than 3 carbon atoms.-

As a tertiary-amino alkyl halide, the more readily available, viz. the chloride, is preferred.

The condensation is preferably effected in anhy- I drous organic medium. An aromatic hydrocarbon, in

1 most cases toluene on account of the level of the boiling point thereof, or an ether may be employed and the; condensation is then generally effected at reflux temper ature, if desired under an inert gas, e.g. nitrogen, atmos-v phere.

However I have foundthatit is particularly desirable to effect condensation in a dialkyl-formamide especially;

and also to obtain better yields. was found particularly desirable where atertiary-aming;

ag rasalkyl halide such as l-dimethylamino 2-ch1oro propane is employed, a ti'ansposit'ic'in'6f the't'ertiaryamino group taking place in the course of the reaction. fI 'he. preferred alkaline condensation agent is sodium amide but metallic sodium or, as th e'case "may be, another alkali metal, in particular as the metal or as a hydride or mixed hydride, hydroxide or carbonate may also be employed.

'The'basic derivative thus obtained may then be converted to an acid addition salt or an oxime or a quaternary ammonium compound according to any conventional method. i

The following examples which are not limiting will illustrate the invention. i

EXAMPLE 1 (a) Z-propionyl 1-'y-dimethylamino-propyl pyrrol In a 500 ml. three-neck flask provided with a central stirring device and a reflux cooler, 12 .3 g. of 2-propionyl pyrrol dissolved in 150 ml. of toluene were placed together with 5 g. of sodium amide under a nitrogen atmosphere. The mixture was boiled for two hours then after reducing the supply of heat, 15 g. of l-chloro 3-dimethylamino propane were'a'dded at one go. The mixtuie wasagain refluxed for two hours.

After cooling, water was added and the toluene layer decanted. Filtering wasnecessary to remove solid impurities. After a new washing with water, several extractions with a percent aqueous solution of acetic acid were effected to extract the desired base from the toluene layer. The extracts were combined and the base was liberated therefrom by adding sodium hydroxide solution then extracted by means of ether. After driving oif ether, the, extract was distilled under a pressure of mm. of mercury, yielding 13.5 g. of a colourless, strongly (b) Acid maleate of base (a) To a solution of 6.5 g. of the oil obtained as described under (a) in 30 ml. of ethyl acetate, a solution of 3 g. of maleic acid in the same solvent was added, and the mixture was boiled for a few minutes. An oil precipitated and set to crystals on the water-bath. After cooling, white crystals as produced were washed with ethyl acetate and anhydrous ether; 8.1 g. thereof were obtained; melting point 142 C.

Recrystallized from isopropanol, the acid maleate was obtained as small colourless scales melting at 142 C.

(c) Oxime of base (a) To 6.5 g. of 3-propionyl l-y-dimethylamino-propyl indol, a solution of 3.5 g. of hydroxylamine hydrochloride in 500 ml. of water was added. A clear solution was obtained; it was heated to reflux for 1 hour. It was then made alkaline with caustic soda lye, whereupon a pasty precipitate was produced. The whole was heated on a water-bath for 30 minutes then cooled under a water stream, the aqueous layer decanted, and the remainder washed by decantation with water, and crystallized from aqueous ethyl alcohol then from methanol. Colourless prisms (2.2 g.) melting at 135-137" C. were obtained.

(d) Methiodide of base (a) To a solution of 3.5 g. of 3-propionyl l-y-dimethylamino-propyl indol in 20 ml. of absolute ethyl alcohol, 4 g. of methyl iodide were added. A crystallized substance gradually formed and was recrystallized from absolute ethyl alcohol. Small transparent, pale yellow plates (3.4 g.) having a melting point of 189 C. were finally obtained.

smelling oil which distilled at 210 C. (temperature of the heating bath).

(b) Metizipdide of, base (a) In an Erlenmeyer flask, 2 g. of base (a) dissolved inanhydrous ethanol were placed together with 3 ml. of methyl iodide. The methiodide thus formed'remained dissolved: after 24 hours, the methiodide was precipitated (4) 3-propionyl 1-y-dimethylamino-propyl indol A suspension of 26 g. of 3-propionyl indol and 7.1 g. of sodium amide'in 200 ml. of xylene was refluxed for 2 hours with stirring, under a nitrogen or hydrogen stream. The sodium compound of 3-propionyl indol gradually precipitated; 25 g. of l-chloro 3-dimethylamino propane'in 50 m1. of xylene were then added and boiling was again proceeded with for l /z'hours, after which only a slight precipitate remained in the solution.

The reaction mixture was washed with water, a slight undissolved' precipitate was filtered off, washing water was discarded and the xylene solution was treated with a mixture of 30 ml. of acetic acid and 60 ml. of water, and finally with water slightly acidified with acetic acid. The aqueous'solutions were combined and made alkaline with sodium hydroxide, and the oily base was extracted with ether. The ethereal solution was washed with water and dried over sodium sulphate, the solvent evaporated and the residue distilled ina retort. 'Between 185 and 205 C. (heating bath temperature) under 1 mm. of mercury, 26 g'. of afyellow oil were collected. 'There was no head fraction and 'onlya. veryslight residue was found in the retort. l I

EXAMPLE 3 Starting from i-chloro 2 dimethylamino ethane instead of l-chloro 3-dimethylamino propane and working in a manner analogous to that described from (a) to (d) in Example 2, the following compounds were prepared successivelyz (a) 3-propionyl l-p-dimethylamino-ethyl indol, a yellow oil' which distilled at 200-210 C. (heating bath temperature) under 1 mm. of mercury;

' (b) The acid maleate of base (a), which recrystallized from isopropanol gave light yellow leaflets melting at 150 'C.;

(c) The oxime of base (a), which recrystallized from methanol gave small colourless crystals melting at C.;

(d) The mcthiodide of base (a), which recrystallized from methanol gave pale yellow prisms melting at 225- 226 C. r

EXAMPLE 4 Starting from 2-chloro l-dimethylamino propane instead of 1 -cliloro S-dimethylamino propane and working in manner analogous to that described under (a) and (b) in Example 2, the following compounds were prepared successively;

a (a) 3-propionyl 1-,B-methyl-fl-dimethylamino-ethyl indol, a light yellow oil which distilled at 200-205 C. (heating bath temperature) under 1 mm. of mercury;

(b The acid maleate of base (a), which recrystallized from isopropyl alcohol gave bigcolourless crystalsmelting at 93 C.'

EXAMPLE 5 Working in a manner analogous to that described in Example 2 but initially substituting 2-propionyl carbazol for l-propionyl indol, the following compounds were prepared successively:

(a) 2-propionyl 9-' -dimethylamino-propyl carbazol, a light yellow oil which crystallized gradually and recrystallized from petroleum ether gave light yellow crystals melting at 62-63 C.;

(b) The hydrochloride of base (a) which recrystallized from water gave pale yellow leaflets melting. at 239 0;;

"or t l (c)'The oxime of base (a) which recrystallized from ethanol gave colourless prisms melting at 168 C.;

(d) The methiodide of base (a) which recrystallized from ethanol gave fine colourless needles melting at 232 C.

' EXAMPLE 6 Working in accordance with Example 5 from 2-propionyl carbazol and l-chloro 2-dimethylamino ethane the following compounds were prepared successively:

(a) 2-propiony1 9-B-dimethylamino-ethyl carbazol which recrystallized from' isopropyl alcohol gave fine, lightyellow crystals melting at 94-95" C.;

'(b) The. hydrochlorideof base (a)'which recrystal-" EXAMPLE 7 Working in accordance with Example 5 fromZ-propionyl carbazol and 2-chloro l-dimethylamino propane, the following compounds were prepared successively:

(a) 2-propionyl 9-13-methyl-B-dimethylaminoethyl carbazol which recrystallized from a mixture of ethyl ether and petroleum ether gave big light yellow crystals melting at 70 C.;

(b) The hydrochloride of base (a), which recrystallized from a mixture of isopropyl alcohol and isopropyl ether gave a crystalline powder melting at 190 C.;

(c) The Oxime of base (a), which recrystallized from ethyl alcohol gave fine transparent needles melting at 175-176" C.;

(d) The methiodide of base (a), which recrystallized from'ethanol gave small, pale yellow crystals melting at 234-235 C.

EXAMPLE 8 (a) 3-dc'etyl I-fi-dimethylamino-ethyl indol Starting from 3-acetyl indol (melting point 188-190 C.) prepared according to Oddos method, 12 g. thereof were dissolved in 40 ml. of anhydrous dimethylformamide and 3.5 g. of sodium amide were stirred into the mixture; after a few minutes, the mixture was gradually heated to 70 C. on a water-bath and the temperature was maintained at that level for 30 minutes. Thereafter 10 g. of l-dimethylamino 2-chloro ethane were introduced into the mixture which was still maintained for 2 hours at 70 C. The mixture was evaporated to dryness in vacuo on a water-bath and treated with water; the base was extracted therefrom with ethyl acetate.

,The extract was then extracted with dilute acetic acid for recovering the base contained therein, the aqueous layer was decanted and made alkaline with caustic soda lye; the base thus set free was finally extracted with ethyl acetate. The extract was Washed with water, it was dried over sodium sulphate, the solvent Was evaporated therefrom, and the residue was distilled in a retort. At 185-205 C. (heating bath temperature) under 0.5 mm. of mercury, 13.1 got an oil were obtained and employed Without purification for the next step.

(b) Acid maleate of compound (a) The 13.1 g. of crude base were treated with 7.3 g. of maleic acid in ethyl acetate. Colourless crystals (17 g.) were collected and recrystallized from absolute ethyl alcohol. Colourless needles melting at 162 C. were ob tained. A

For analysis purposes, a sample thereof was recrystallized from percent ethyl alcohol.

Percent Percent Percent Calculated f0! C14H1& 20.C4H4O4 62. 41 6 40 8. 09 Found 62.51 6 52 I 8.17 62. 47 6 59 8.11

(c) Oxime corresponding to compound (a) Percent Percent Percent Calculated for UuHmNsO g2. 1g

Fmmd 9109 71 7e 17: 15"

EXAMPLE 9 Following the procedure of Example 8 but substituting 3-phenylacetyl indol (prepared according to Oddosj method: white crystals melting at 207 C.) for 3-acetyl' indol, the following compounds were obtained successively:

(a) B-phenylacetyl l-B-dimethylamino-ethyl indol, an

oil which distilled at 220240 C. (heating bath temperature) under 0.5 mm. of mercury and gave brightpale yellow crystals melting at 93 C. after crystallizationfrom cyclohexane (and also after a subsequent recrystal lization from isopropanol).

Percent Percent Percent 1 Calculated for CzzHzzNzO gig (b) Acid maleate of compound (a), which recrystal-. lized from anhydrous ethanol had a melting point of'148.- 149 C. (matted, bright crystals).

o, H, N,

Percent Percent Percent Calculated for CziHztNsO 23.3? 2.23 53 Fmmd 68:15 6127 alts (c) Oxime corresponding to compound (a); bright leaflets melting at 204 C. after recrystallization'from ethyl acetate. j

Following the procedure of Example 8 but substituting 3-propionyl indol for 3-acetyl indol. and l-diethylamino 2-chloro ethane for I l-dimethylamino-chloro ethane, the following compounds were prepared successively: I

essence (a) 3-propionyl l-fi-diethylamino ethyl indol, a. rel.-

low oil distilling at ZQO220 C. (heating bath temperature) under a. pressure of 0.4 mm. of mercury;

(b) Acid maleate of compound (a), colourless prisms melting at"189 C. after recrystallization from isopropianol Eo'r. analysis, a sample was dried at 80." C. under 1mm. of mercury.

Percent Percent -55.. 64. 92 7. 26 F d V l 64. 81 7. 49 1 64.77 7.42

(c) Oxime corresponding to compound (a), colourless s'cales melting at 136 C. after recrystallization from 95 percent'ethyl alcohol. For analysis. a sample was dried a fitlf under of mercury.

o, H, Percent Percent C810 med gramme 71. 2s a. 45 71.13 1.01

' tanner (a) 3-prapionyl I-B-methyl-fl-dimethylamino-ethyl inalol 1 and acid maleate thereof Lnto an ice-cooled solution of 13 g. of 3-propionyl magi in4q 151. of anhydrous dirnethyl formarnide, 3.5 g. o'f s odium amide werestirred; The ice cooling bath was then withdrawn and the mixture allowed to'c'o'me' back to ambient temperature, after which 2.9 g. of l-dimethylamino 2 ch l o ro propane were dropped into the mixture. The mixture was'then heated to 40-45 C., while stirring, tor 24 hours. l

"The heating period indicated was found to correspond to "the best -conversion rate but as a matter of fact the desired product could also be obtained by heating for a shorter period; for example 4 hours, and subsequently recovering unreacted starting material.

The reaction mixture .was then evaporated, to dryness in vacuo to drive off dimethylforrnamide, treated with water then extracted with ethyl acetate, and further treatrnent waseflected as described in Example 8(a).

By distilling in a retort the desired base was obtained with a yield of 75% as a light yellow oil'distilling 'at 1910-2000. (heating bath temperature) under 0.5 mm. of mercury. By treating the crude base thus obtained with .maleie acid in ethyl acetate, colourless crystals of acid maleate melting at 94-99 C. were obtained with a yield of 90 percent. A mixture thereof with crystals obtained from the. production of the base in toluene medium showed'no depression of the melting point.

raster wall wanbeinag it was washed by decantation several t imes withwater. 'Upo'n crystallization from 50 it'riit ethyl alcohol; small colourless needles (2.6 g.) melting at 162 (Kofler) were obtained.

Ea anal sis a am le F Yl?1l S q 1 5 1e ona). res ii a 89. ques of mercury.

0, H, Percent Percent lcul te or CmHu u 3 .3 3;; Emma-4 EXAMPLE 12 3-f0rmyl I-fl-dimethylamino-ethyl indol and acid ma leate thereof A mixture of 3 -formyl indol (12.9 g.), l-chloro 2- dimethylamino ethane (11.4 g.), powdered sodium amide 6 g.)"'and dimethyl form amide ml.) was stiqed.

r 4 hours at 4 C- h s id aider as fi e Q n t e ubseq e P o edu e wa $4 w l be described subsequently in Example 17.

3-formyl l-fl-dimethylamino-ethyl'indol was obtained as an oil boiling at C. under a pressure of 0.4 mm. (temperature of the heating bath), and the acid maleate thereof, "after -recrystallization from isoptopanol, had'a melting point of '127 'C. The yield (reckoned on 3- forrnyf'indbl') of; said acid maleate amounted to 69- percnt Results of t he analysis (acid maleate):

1 H1 NI Percent Percent Percent Calculated for C11H20N205 6i. g2 0g 41:

6 4 .1 .5 Fmmd 61.67 6.01 4 an;

The starting material, 3-forrnyl indol was prepared according to TysonJ Chem.Soc., 1952, 74.2274} EXAMPLE 13 3-f0rmyl. I-fl-dimcthylnmino-ethyl indol oxime Analysis 7 0, per- H, per- N, percent cent cent- Calculated for CmHnNaO range no 18.17 6. r .52 17.88 Fmmd EXAMPLE 14 I Acid maleate of 3-acety l 1-;3-dimethylamino-ethyl indol.

oxime A solution in ethyl acetate of 3-acetyl l-fl-dimethyl amino thyl indoloxime (2.1 g.) prepared accordi'ngito. Example 8(a) was admixed with a solution of maleieacid (1.1 g.) in ethyl acetate. An oily precipitatewhich 1y crystallized was produced. It was filtered oil and after recrystallization from absolute ethanol yielded amber-like crystals (2.4 g.) having a melting point, of: 161 C. (dec.)

assures.

Analysis 0,156;- Hitteris, per

cent cent cent calculated for cisHzmaOs gs; 1 gig Fmmd '59: 91 6:55 11109 EXAMPLE Acid maleate of 3-propionyl I-B-dimethylamino-ethyl indol oxime A solution of the oxime (15 g.) prepared in accordance with Example 3(c), in ethyl acetate (100 ml.) was combined with a solution of maleic acid (7.4 g.) in ethyl acetate (100 'ml.) at a temperature in the neighborhood of the boiling point of. ethyl acetate. A substance crystallized out almost immediately; it was separated and re crystallized from 95 percent ethyl alcohol. Fine crystals (19.8 g.) having a melting point of 161 C. (dec.) were obtained.

Analysis gi gg 1 3?- tilled after evaporation of ethyl acetate. At a temper ature of 190-210 C. under 0.4 mm. of mercury (heating bath temperature), an oil (30.5 g.) was obtained. gif for CWHZENSOE 281252 213% ii A hot solution thereof in ethyl acetate was admixed 60-84 11-09 with a hot solution of maleic acid (14 g.) inthe same solvent. White crystals separated out and were recrys- EXAMPLEQM tallized from 95 percent ethyl alcohol. The final crys-- 3 y -fiy "ldOl oxlme tals of acid maleate (39.6 g.) had a melting point of A solution of the acid maleate 14 g.) of 3-butyryl l56157. l-p-dimethylamino-ethyl indol, hydroxylamine hydrochloride (15 g.), potassium hydroxide (40 g.), Water (160 Analysis (acid maleate) C,per- H, per- N, perml.) and ethyl alcohol (200 ml.) was boiled for 3 hours. 1 cent lent cent The major portion of alcohol was then driven ofi in vacuum on a water bath and the residue poured into calculated OMHEBNZO gag: Z: 3: water; a pasty product was precipitated and crystallized 64. 97 I 7. 32 7. 43 ina few minutes It was filtered oif and recrystallized 7 from 70 p c ethyl a Needle shaped crystals The starting material, 3-valeroyl indol, was prepared e) havmg a melflng P of w according to Oddos synthesis. tamed 40 EXAMPLE 1:; Analysis 3? 5?" (a) 3-va'ler0yl l-fl-dimethylamino-cthyl indol oxinie The technique was the same as in Example 16,1116 Calculated for CmHzaNsO 70. 29 8.48 15.37 starting materials being acid maleate (19.4 g.) of 3-val- Found Z8: g: eroyl l-fi-dimethylamino-ethyl indol, hydroxylamine hyr drochloride (20 g.), potassium hydroxide g.), Water (b) Acid maleate of base (a) (200 m1.) and ethyl alcohol (240 g.). The final base W38 A'solution of base (a) (4.0 g.) in ethyl acetate and recrystaulzed m Percenf ethYl alcohol- Blgght a solution of maleic acid (1.8 g.) in ethyl acetate'were crystals havmg a meltmg Pomt of 107-408 combined at a temperature in the neighbourhood of the 60 were obtamed' boiling point of ethyl acetate. An oily product precipitated and quickly crystallized on cooling. It was filtered Analysis 5 52" l gi OE and recrystallized from absolute ethanol. White 7 crystals (+8 g.) havmg a melting point of 160 C. (dec.) calculated for o g N o 3.22 were obtamedf v x Emma 71119 81 so '14159 Analysis O,per- H,per- N, percent cent (b) Acid maleate of base (a) v g calculated for g q o 1 7 99 10,79 Combining a solution of base in hot ethyl Found 61-57 7.19 10.76 acetate and a solut1on'of maleic'acid (2.3 g.) in hot i v ethyl acetate as.described in Example 16 (b), I obtained ture from which White crystals (6.3 g.) having a The starting material .3-butyryl l-p-dimethylarmnoa i a ethyl indol was prepared by same procedure as will be meltmg Pomt of 152 separated on coohng described below in Example 17, from Za-bu'tyryl indol 1 H (MLPJ 175 C.; xylene) produced according to Oddos Ana ysis eiii ei'ii e'eiii synthesis. The acid maleate of 3-butyryl l-p-dimethyl g V amino-ethyl indol was found to have a melting point of Calculated for o,,HN;05 62.51 7. 25 10.42 140 C., the results of analysis in respect thereof being Fpund i8 i8 1; as follows: I v

Analysis O,per- H,per- N, perv V EXAMPLE 19 cent cent can. (a) Add maleate of 3-butyryl 1- -pyrr0lidin0-propi0nyl cgxeuimdmrcnnm ofi 64. 14 -7.00 7.48. l Found. .j. :82 g; Sodium amide (3.5 g.) was introduced while stirring,; 15'; at a temperature below 30- C.,. into a solution of 3-" V "EXAMPLE 17 thereof Powdered sodium amide (10, g.) was added while stirring and with moisture excluded, to a'solution of 3- valeroyl indol (30.2 g.) in anhydrous dimethyl formamide ml.). The inner temperature was limited to 60" C. by means of a cool water bath then after cooling to too temperatures l-chloro Z-dimethylamino ethane (19.5) was added. The mixture was left to room temperature for 30 minutes then heated to '6570 C. for 2 hours. The solid residue was filtered otf, dimethyl formamide was evaporated in vacuum on a water-bath, the residue taken up in ethyl acetate and water, the organic phase extracted with dilute acetic acid, and the base set free from the aqueous thereto.

The base was extracted with ethyl acetate, the extract washed with water,'dried over sodium sulphate and disphase by adding caustic soda lye 11 I2 butyryl indol (11.2 g. in dimethylformamide; the d spersion thus produced was heated to-60 for 15 m 1n.- Analysis 0, pep H N, pop utes "then cooled to 20 C., and l-chloro 3-pyrrol1dmo cent on: cent propane (9.25 g.) was added thereto. The mixture was a n I stirred at room temperature for 30 minutes then at 65-70 5 galcuiated for CliHnNzOlnr Z8 g; C. for 2 hours. 71:58 71 82 9178 After working up as described in Example 17, the base was distilled, yielding at a temperature of 180200' C- (1;) A id maleate of base (a) under 0.1 mm. of mercury (heating bath temperature) 1 d f b 4 a light yellow oil (15 g.) which was treated with maleic 10 6 1 s g fial'e hrlom tase (1i?) gil) acid (6.1 g.) dissolved in the same amount of isopropyl and ma acld 5 M i g 'g alcohol. Big bright colourless crystals (15.4 g.) having 232 :3 5? g g g izig gfig g gg g gg gzs f b'-d coolin. a meltm" point of 103 C were 0 tame on g liz-ed from absolute ethanol. Big rose prisms (5 g.) having a melting point of 163 C. were finally obtained. Analysis G, pezr- H, per- N, per- 0811 cen COD Analysis 0, per- H, per- N, per- Calculatedtor ownaNtooinioi 66.64 7.30 6.76 cent cent cent F and 66.89 7.42 6.88 67-03 CaleulatedforC 1H N 0 C4H404 62.60 0.51 0.90 2 is (b) Oxime corresponding to base (a) Acid maleate of 3-butyryl l-y-pyrrolidino-propyl 10 Oxim wrrespvnding to base g.), hydroxylamrne hydrochloride (10 g.), potass um hy- 3130131011 1 5 mo1-Pho1ino ethy1 indol (4 droxlde (45 water (100 and ethyl alcohol (120 droxylamine hydrochloride (5.6 g.), potassium hydroxide ml.) were refluxed together for 3 hours. Towards the (14 g), water (55 m and ethyl alcohol (70 m were and the heatmg Perlod deslred oxlme, P F refluxed together for 3 hours. The reaction mixture was as Whlte needl The Suspenslon was cPoledi h crystals made acid with a slight excess of acetic acid, then neuwere filtered f and {eerystanlzed from. 95 F tralized with a saturated aqueous solution of sodium carcent ethyl alcohol. Bright, white leaflets (5.3 g.) having bonate; an oil precipitated and was extracted with a meltmg P of 165 Were obtmned' ethyl acetate. The solvent was evaporated from the extract and a brown yellow oil (1.7 g.) was obtained. Analysis g gg' gi 3 (d) Acid maleate of oxime (c) 5 The oil obtained according to (c) was reacted with Calculated for ONHNNQO g 2- the required amount of maleic acid in hot ethyl acetate. Found 13156 On cooling a brown oil precipitated and crystallized gradually. It was recrystallized twice from absolute ethanol, (c) d )maleate of mime (b) 40 finally yielding fine cream-coloured crystals; M.P. 152 C. The acid maleate was obtained quantitatively from Analysis .1 .1 2 maleic acid (1.2 g.) and the above oxime (3 g.) in'ethyl acetate. It was recrystallized from absolute ethanol, yielding colourless prisms; MI. 148 C. Calculatedmr 281% 2:32

Fmmd 1 ,.,.-'N, Analym ce iz edi? .193? To compounds obtained according to this invention are generally little toxic and act on central nervous system Calculated for C19H27N30.C4H404 64.31 7.28 9.78 and/or Cardin-vascular system. Found t; g; The pharmacodynarnic activity of a few typical compounds will be described below; the compounds in point corres' 0nd to the eneral formula (Ii) Acid oxalate of oxime. (b) p 7 g Produced in absolute ethanol from stoichiometric fiamounts of the above oxime and oxalic acid, then recrystallized from water, the acid oxalate had a melting N point of 191 C. 7 4m EXAMPLE 2o (LIH I (a) 3-pr0pz'onyl J-B-mo rpholino-ethyl indol i Sodium amide (3.2 g.) was stirred into 'a solution of 1110 CH 3-propionyl indol (9 g.) in dimethyl formamide (35 m1.) at a temperature below 30 C. and the dispersion was fi ig i g f; j then heated to 60 C. for 15 minutes. It was cooled for im? i i fz i fi h w m thereafter to 20 C. then l-chloro 2 morpholin'o ethane g e o owmg were (8.5 g.) was added thereto and the mixture was stirred obtamed: for 30 minutes at room temperature then for 2 hours at Maximum LD 50 LD 100 65-70 C. R tolerated dose (mg/kg.) (mg/k3,)

After working up as described in Example 17, the (mg/kg) base was distilled at 180-200 C. under 0.1 mm. of mercury (heating bath temperature). A yellow oil (86 g.) off, l,, g g gwhich solidified on cooling was obtained. A sample there- 3 15 above 200: oi crystallized from isopropyl ether gave bright white fij i z 5 55 leaflets havinga melting point of. 115 C.

1 Additionally, the'LD 0 was found 'to be (if-about mg./kg. as to the second and third compounds when administered intravenously to mice.

The compounds in which R stands for H, CH C H or II-C3H7 were found, upon intravenous administration 5 to dogs, to produce an increase of arterial blood resulting from a peripheral vasoconstriction.

' -14 hypertensive chemicals, hypertensive threshold doses' of adrenaline (0.001 mg./kg.) and nor-adrenaline j(0.00'l mg./kg.), and hypotensive threshold doses of 'acetyl choline (0.002.mg./kg.) and histamine (0.002 mgL/kg.) were administered intravenously to dogs anesthetized with chloralose; v

The results are tabulated below:

It Adrenaline, 0.001 mgJltg. nor-adren., 0.001 Acct. choline, 0.002,; I Histamine, 0.002

V s-l -l g-l g- H Hypertension extenu- As with adrenaline" Hypotenslon stopped Hypotension extenu ated with more than with more than 0.1 ated with more than 1 mgJkg. mg. g. 1 mgJkg. O Little alter Little altered A litt e extenuated Lowered with more v v i with more than 1 than 3 mgJkg.

. mg. g. Om. do do Stopped with more Stopped with more than 1-2 mgJkg. than 10 mgi/kg. n-Q-Hs (in do Stopped with more Stopped wit more than 0.3-1 mgJkg. than 0.3 m g/kg. orm (in rln Little l r Little aitere Specifically the animals forexperiments being dogs anesthetized with chloralose, the arterial blood pressure was measured in the central end of carotid by means of a Ludwig pressure-gauge. The compounds were injected through a cannula placed in the external saphenous vein.

In respect of each compound, the lowest dose capable of causing a slight increase in arterial blood pressure (threshold dose) was measured, then with the dose causing an increase of arterial blood pressure by'about 50 percent the time taken for such pressure to come back to its initial level was measured. The results are tabulated below:

. With a view to determining any action of the com- In other words, the first four compounds interfere but little with the action of adrenaline or nor-adrenaline, but

are endowed with atropin-like and antihistaminic prop:

rate from a Jouve'lets pump.

The therapeutic index may be considered as the ratio' between LD 50 (subcutaneous administration to mice) and the dose which administered intravenously causes an increase by 50 percent of dogs arterial blood pressure. The therapeutic indices will then be as follows R Therapeutic index "H' so OHL p V V 875 04H! i n-OJL' I: 1.

In the following table are summarized the properties useful for therapeutic purposes, of typical oximes of the pounds according to this invention 'on' hypotensive and general formula 1 I-i'OH i a B1 R: Uses -CH C Hz-NCHa): Hypertensive agent. CH2--CHr-N CH3): Local vasoconstrictive agent. CHr-C He -CHz-CH2N(GH3)2 D0. CHQ-CHI CHI CHr-CH2N(CH3)2 D o. GH:OHr-CH:CH;.. CH:--OH:N(OH); Sedative agent for central nervous system.

GH CH,CHr-N(OHr)i Depressive agent for cardio vascular system; CHLOE; -CHg-O HN(CH;)9 Hypertensive agent.

OH:.CH| -CHgCH:-0H,N(CH;)1.... Depressive agent for central nervous system.

cream as 15 The oximes' produced accordingto this'inve'ntion may be employed as such or as acid addition salts thereof in local applications (nasal instillations, sprays, aerosols, collyriums) or in general applications (as solutions in aqueous solvents or organic solvents such as oils or ethyl- 5 ene glycol, for intramuscular or intravenous admimstraa tion).

What I claim is:

1. A member selected from the class consisting of oximes and acid addition salts of said oximes with pharmaceutically acceptable acids, said oximes having the general formula Am wherein R is a group selected from the class consisting of -CH3, CH2CH3, ca -CH, err -0H R is an alkylene group having two to three carbon atoms and Am is selected from the class consisting of dimethylamino, diethylamino, morpholino and pyrrolidino, said acids being selected from the class consisting of hydrochloric, phosphoric, sulphuric, oxalic, maleic, furnaric, succinie, citric, tartaric and gluconic acids.

2. 3-propionyl l-p-dimethylamino ethyl indol oxime of and 3. 3-acetyl l-fi-dimethylamino-ethyl indol oxime of the formula 4; 3-butyryl' l fl-dimethylamino-ethyl indol oxime of the formula C-CHrCHa-C H:

N-OK

N (ha (:JHa

5. 3-propionyl l-y-dimethylamino-propyl indol oxime of the formula C-CHr-CHs 6. 3-propionyl 1-fi-methyl-fi-dimethylamino-ethyl indol oxime of the formula v References Cited in the file of this patent UNITED STATES PATENTS 2,528,940 Wright Nov. 7, 1950 2,616,896 Weisblat et al Nov. 4, 1952 2,687,414 Cusic Aug. 24, 1954 FOREIGN PATENTS 720,298 Great Britain Dec. 15, 1954 OTHER REFERENCES Buu-Hoi et a1.: Jour. Org. Chem, vol. 16, pp. 1198- Mann et a1.: Jour. Chem. Soc. (London), pp. 670-671 

1. A MEMBER SELECTED FROM THR CLASS CONSISTING OF OXIMES AND ACID ADDITION SALTS OF SAID OXIMES WITH PHARMACEUTICALLY ACCEPTABLE ACIDS, SAID OXIMES HAVING THE GENERAL FORMULA 